Science

Intro

The Gardini Lab works to understand how mammalian genomes are expressed during cell fate specification, cellular homeostasis and tumorigenesis.

Regulating mammalian transcription is a multi-layered process that revolves around the activity of the basal transcriptional machinery (RNAPII and associated complexes). Within the nucleus, RNAPII loading and processivity is modulated by nucleosome spacing (accessibility), histone modifications, phosphorylation switches, noncoding cis-regulatory elements and chromatin architecture. We integrate omics, genetics and biochemistry approaches to gain a holistic view of gene regulatory mechanisms.

Global transcriptional regulation by Nuclear Phosphatases

Transcription of coding and noncoding RNAs is modulated by phosphorylation-dependent switches and checkpoints. Phospho-checkpoints ensure a paced, controlled workflow for RNA Polymerase II and safeguard transcriptome integrity.

Subverting all rules of tissue homeostasis, tumors hype-up transcription. And they often do so by seizing control of phosho-checkpoints to boost initiation, elongation and RNA processing.

While many of the kinase regulators of transcription (CDK7, CDK9, CDK12, CDK13) have been characterized over the past 2 decades, the lab in focused primarily on chromatin-bound phosphatases. We identified PP2A as a robust modulator of RNA polymerase pausing and we strive to understand how PP2A is recruited, regulated and decommissioned during the transcription cycle.

Enhancer regulation during cell-fate commitment

Any process of cell differentiation entails widespread, radical transcriptomic changes. Transcription factors, chromatin remodelers, and the RNA Pol II machinery orchestrate the timely activation of hundreds of protein coding genes. To establish and maintain new gene programs, mammalian cells utilize noncoding cis-regulatory elements known as 'enhancers'. The lab studies how enhancers operate as key initiators of cell identity changes, using a variety of model systems, from cortical neurogenesis to adult hematopoiesis.

Enhancer malfunction results in a broad spectrum of disorders, from cancer to thalassemia, from neurodevelopmental syndromes to cardiovascular diseases.

Structure-function studies of the Integrator complex

The Integrator protein complex is a massive (1MDa) Pol2-associated machinery that was only identified in 2005. Integrator is likely the most versatile gene regulation platform in all metazoans and is still poorly studied. The lab has pioneered the biochemical and functional characterization of this complex. We employ genetic, genomic and proteomic tools to dissect the roles of Integrator in gene regulation, RNA processing, genome organization and DNA repair.

Integrator subunits are found deleted in multiple cancers and are mutated in a variety of severe neuro-developmental disorders.

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